Drug-resistance in cancer is the major impediment to a successful treatment of cancer. Multidrug-resistance (MDR) in cancer cells is a phenotype whereby cells display a reduced sensitivity to chemotherapeutic compounds based on several mechanisms in particular including an increase in drug efflux (Han, L. et al., Nat Prod Res, 2015, 1-4). Said multidrug-resistance can be a pre-existing one and, thus, evident at the onset of therapy (intrinsic) or alternatively be acquired after onset of therapy.
Members of the family of membrane proteins named ATP binding cassette (ABC transporter proteins) transporters or pumps usually consist of four domains which include two trans-membrane domains (TMDs) and two nucleotide binding domains (NBDs) as minimum functional unit to transport a substrate such as a chemotherapeutic compound triggered by ATP binding and respective hydrolysis. Members of said family are notorious mediators of MDR, actively effluxing a wide range of therapeutic compounds such as chemotherapeutic compounds irrespective of their concentration gradient. This significantly lowers their intracellular concentration and, thus, their therapeutic effect in those cells. A prominent ABC transporter protein subfamily reported to modulate anticancer drug uptake is the “B” subfamily in particular with P-glycoprotein (P-gp, MDR1, or ABCB1) or ABCB5 including respective isoforms. Besides, common ABC transporters include the “C” subfamily such as with multidrug-resistance protein (MRP1 or ABCC1) and the “G”-subfamily such as with breast cancer resistance protein (ABCG2 or MXR).
ABC transporter proteins have been found to be constitutively expressed and overexpressed, respectively, in many multidrug-resistant cancers, wherein P-glycoprotein is considered for being a key player in the multidrug-resistant phenotype in cancer. Thereby, the expression of P-glycoprotein in multidrug-resistant cancer cells seems to be regulated by a wide range of factors including hypoxia, metabolic acidosis, generation of reactive oxygen species, namely P-glycoprotein is considered for being an important responder to chemical insult or environmental influences on cancer (Callaghan, R. et al., Drug Metab Dispos 2014, 42:623-31).
Expression and overexpression, respectively, of P-glycoprotein has been found in various types of cancers and cancer cells, respectively, with the multidrug-resistant phenotype, such as MCF-7 breast (Kim, T. H. et al., Biochim Biophys Acta, 2014, 1840:615-25, A549 lung cancer (Xu, L. et al., Oncol Lett, 2014, 7:387-392), and HCT-8 colon cancer (Xing, Y. et al., J Dig Dis, 2014, 15:246-59). Such expression and overexpression, respectively, of P-glycoprotein is usually accompanied by a resistance against commonly used and standard chemotherapeutic compounds such as anthracyclines, vinca alkaloids, topoisomerase-I and -II inhibitors, taxanes and the like, for example against doxorubicin or paclitaxel (taxol). Its broad specificity has been the subject of major attempts to inhibit said protein pump activity and to sensitize the cells towards chemotherapeutic compounds (Callaghan, R. et al., Drug Metab Dispos 2014, 42:623-31). Accordingly, a strategy is to identify small-molecules that either act as direct P-glycoprotein inhibitors or compete with chemotherapeutic compounds for transport. Furthermore, the resolved structure of P-glycoprotein further revealed a molecular basis for poly-specific drug binding crucial for the lead optimization of chemotherapeutic compounds and MDR modulators (Aller, S. G. et al., Science, 2009, 323:1718-22).
MDR modulators developed so far, however, fail to provide sufficient inhibition of ABC transporter proteins such as P-glycoprotein and/or did not demonstrate sufficient clinical utility in overcoming multidrug-resistance. Besides, most of the ABC transporter protein inhibitors described so far have been initially developed for the treatment of other diseases than cancer like verapamil and these main drug activities may, thus, appear as non-tolerable side effects in cancer therapy. Unfortunately, progress in this area has been rather slow although having effective treatment options for multidrug-resistant cancer gets more and more important today.
Pro- and anti-apoptotic proteins have been associated with multi-drug resistant cancer, too. Apoptosis is a defined program of cell death with molecular and morphologic changes such as DNA fragmentation, formation of cytoplasmic apoptotic bodies and plasma membrane changes. It is markedly influenced by various genes and respective proteins, which may be mutated or dysfunctionally regulated such as pro-apoptotic proteins may be absent or there may be an enhanced expression of anti-apoptotic proteins or mutations which inactivate pro-apoptotic proteins and activate anti-apoptotic proteins in cancer cells. In this context, it has been especially found that the expression of mutant and wild-type p53 or Bcl-2-family members and other proteins associated with the control of apoptosis in cells may have a significant impact on the clinical sensitivity of cancer cells. Thus, these proteins are also possible targets in order to overcome multidrug-resistance. For example, cancer cells lacking cell death mediators Bax and Bak have been reported to develop drug-resistance to elude various apoptosis-stimuli (Westphal, D. et al., Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2011, 1813:521-531). Apart from the apoptotic proteins, pro-apoptotic tumor suppressor protein p53 proved to be a sensor of cellular stress and also a critical initiator of apoptosis (Gudkov, A. V. and Komarova, E. A., Nature Reviews Cancer 2003, 3:117-129). The high frequency of p53 mutations is expected to lead to a drug resistance of cancer cells, too (Branch, P. et al., Oncogene, 2000, 19:3138-3145, Fan, S. et al. Cancer research, 1994, 54:5824-5830).
Consequently, there is a strong need for methods and means allowing for an effective therapeutic treatment especially of multidrug-resistant cancer and cancer cells with a multidrug-resistant phenotype, respectively. In particular, efficacious treatment options are urgently required for specifically treating subjects with multidrug-resistant cancer with expression or overexpression of ABC transporter proteins, decreased expression of pro-apoptotic proteins and/or increased expression of anti-apoptotic proteins, i.e. for treating said specific subgroups of subjects among subjects with cancer.